Abstract Study question Will acetate treatment ameliorate doxorubicin-induced testicular toxicity when used concomitantly? Summary answer Acetate ameliorated doxorubicin-induced testicular toxicity by modulating Nrf2/NFkB and apoptotic signaling. What is known already Doxorubicin is an antineoplastic agent that is effective in the management of several forms of cancers. However, a major limitation of this drug is its testicular toxicity. Studies have revealed that doxorubicin impairs male fertility by inducing testicular injury via downregulation of Nrf2 and upregulation of NFkB and apoptotic signaling. On the other hand, acetate upregulates Nrf2 and downregulates NFkB and apoptotic signaling. Yet, no study has reported the impact of acetate on doxorubicin-induced testicular toxicity. Study design, size, duration This is a prospective experimental study using animal model. Thirty two sexually mature litter-mate male Wistar rats of comparable weight were used for the study. The study lasted 8 weeks. Participants/materials, setting, methods Animals were acclimatized for two weeks, then randomized into four groups (n = 8). The control rats received 0.5mL of distilled water as vehicle p.o for 14 days, acetate-treated rats received 200 mg/kg/day of acetate p.o for 14 days, doxorubicin-treated rats received 7 mg/kg of doxorubicin i.p on day 8, while acetate + doxorubicin-treated rats received treatment as acetate-treated and doxorubicin-treated. The doses of drugs used were the Human Equivalent doses for rats. Main results and the role of chance Acetate ameliorated doxorubicin-induced rise in testicular activities of gamma glutamyl transferase, lactate dehydrogenase activity, and lactate levels. Also, acetate ameliorated doxorubicin-induced decline in the activities of testicular superoxide dismutase and catalase, and glutathione and Nrf2 concentrations. Acetate also alleviated doxorubicin-induced rise in testicular MPO activities, malondialdehyde, TNF-α, IL-1β, and NF-kB levels. More so, acetate ameliorated doxorubicin-induced reduction in spermatogenic indices and sperm quality, circulatory levels of FSH, LH, and testosterone, and testicular concentrations of 3β-HSD, 17β-HSD, and testosterone. These events were associated with dampening of doxorubicin-induced upregulation of Bax, caspase 3 and caspase 9 activities and doxorubicin-induced downregulation of BCl-2 by acetate. Limitations, reasons for caution This study was conducted in a rat model; therefore the results of the present study should be extrapolated to human with caution. Clinical trials are recommended to validate these findings. Wider implications of the findings The present study demonstrated the ameliorative effect of acetate treatment on doxorubicin-induced testicular toxicity. These findings provide substantive evidence of the possible protective role of acetate in doxorubicin-induced testicular toxicity. Trial registration number Not applicable